Parvoviruses Case File

Parvoviruses Case File

Eugene C.Toy, MD, Cynthia Debord, PHD, Audrey Wanger, PHD, Gilbert Castro, PHD, James D. Kettering, PHD, Donald Briscoe, MD

CASE 33

An 8-year-old boy is brought in to the physician’s office with a 3-day history of fever and a rash. He has also had a mild sore throat and felt somewhat fatigued. His mother is concerned that he could have “scarlet fever.” The rash started on his face and then spread to his arms and legs. He has only been given acetaminophen for the fever. He takes no other medications, has no known allergies, has no significant medical history, and has had no contact with anyone known to be ill. On examination, his temperature is 37.7°C (99.8°F), and his other vital signs are normal. His cheeks are notably red, almost as if they had been slapped. His pharynx is normal appearing, and the remainder of his head and neck exam is normal. On his extremities there is a fine, erythematous, maculopapular rash but no vesicles or petechiae. A rapid group A streptococcal antigen test done in the office is negative.

◆ What virus is the likely cause of this illness?

◆ In which human cells does this virus cause lytic infections?

ANSWERS TO CASE 33: PARVOVIRUSES

Summary: An 8-year-old boy with fever and “slapped cheek” appearance has erythema infectiosum or fifth disease.

◆ Most likely viral cause of this illness: Infection with parvovirus B19

◆ Human cells in which the virus causes lytic infections: Mitotically active erythroid precursor cells

CLINICAL CORRELATION

Parvovirus B19 is the only parvovirus known to cause disease in humans. Infection occurs typically in school-age children resulting in a mild febrile upper respiratory illness followed by an exanthematous rash on the face or “slapped cheek” appearance which later spreads to the extremities. It is classically described as fifth disease because it was the fifth childhood exanthem to be described after varicella, rubella, roseola, and measles. Adults are less commonly infected, and primarily present with polyarthritis of the hands, knees, and ankles, occurring with or without rash. Chronic infection occurs in immunodeficient patients with more serious consequences, such as severe anemia and aplastic crisis. Additionally, infection occurring in pregnant seronegative mothers can lead to serious infection and fetal death.

APPROACH TO SUSPECTED PARVOVIRAL INFECTION

Objectives

1. Be able to describe the characteristics of the virus.
2. Be able to describe the strategies for prevention and treatment of the infection.

Definitions

Exanthem: An eruptive disease or eruptive fever appearing on the skin.

Enanthem: An eruptive disease appearing on mucous membranes.

Petechiae: Tiny reddish or purplish spots containing blood and appearing on the skin or mucous membranes.

Hydrops fetalis: Serious edema of the fetus which can result in congestive heart failure.

Erythroid progenitor cells: Precursors to erythrocytes.

DISCUSSION

Characteristics of Parvovirus That Impact Transmission

Parvoviruses are small, nonenveloped viruses with a linear, singlestranded DNA genome. They are the smallest of the DNA animal viruses, and their virions contain either a positive- or negative-sense copy of the viral genome. Parvovirus B19 belongs to the Parvoviridae family and is the only parvovirus known to cause human disease. It is spread from person to person by respiratory and oral secretions, replicating first in the nasopharynx, then spreading by viremia to the bone marrow. It binds to the erythrocyte blood group P antigen on erythroid precursor cells and is internalized through coated pits. After internalization, the viral DNA is uncoated and transported to the nucleus, where a complementary DNA strand is created by the host DNA polymerase. Inverted repeat sequences on the 5′ and 3′ ends of the viral DNA genome fold back and hybridize to provide a primer for the initiation of DNA replication. The resultant double-stranded viral DNA is then further replicated and transcribed via host cell machinery, and newly formed virions are assembled in the nucleus. Additionally, other factors only available in the S phase of mitosis are required for parvoviral replication. The newly assembled infectious particles are then released by lysis of the host nuclear and cytoplasmic membranes, resulting in cell death. The major site for parvoviral replication is in adult bone marrow and fetal liver cells. Because replication in these cells results in cell lysis and death, there is a disruption of red cell production and resultant anemia that occurs with viral infection.

Clinical symptoms caused by parvovirus B19 are related to the immune system response to the infection. The most common clinical illness associated with parvovirus B19 is erythema infectiosum, or fifth disease. It is commonly seen in children and usually causes a biphasic infection with mild upper respiratory symptoms, low-grade or no fever, and a rash. The initial stage lasts for approximately 1 week and involves the infection and killing of erythroid cells followed by viremic spread. This stage is the infectious stage and produces flu-like symptoms with mild fever and upper-respiratory symptoms. The second stage of infection is immune-mediated, with the formation of host antibody-virus immune complexes, a reduction in viremia, and the emergence of a spreading lacy skin rash and/or anthralgias. The rash usually starts on the face and is classically described as causing a “slapped cheek” appearance. A maculopapular rash will then frequently develop on the extremities. Adults may get a rash, but more often develop arthralgias or frank arthritis. The production of rash, arthralgias, and arthritis are all results of circulating antibodyvirus immune complexes. These symptoms are usually self-limited. Yet, persistent infections can occur in immune-compromised hosts who fail to produce virus-neutralizing antibodies, because host antibody-mediated immunity is necessary for defense against the infection and prevention of reinfections.

More rare but potentially life-threatening complications of parvovirus B19 infection can occur. Aplastic crisis can occur in hosts with a chronic hemolytic anemia, such as sickle cell disease or other acquired hemolytic anemias. In this setting, the combination of viral replication in red cell precursors along with the reduced circulatory life span of existing red cells may result in a profound anemia. Additionally, parvoviral B19 infection in immunodeficient patients can result in persistent infections with chronic bone marrow suppression and anemia. There is also an increased risk of fetal loss because of anemia caused by transplacental infection of the fetus when a seronegative mother becomes infected during pregnancy. Fetal parvoviral infection can result in hydrops fetalis, severe anemia, and often, fetal death before the third trimester. The fetus of a seropositive mother is protected from infection by maternal circulating antibodies.

Diagnosis

Diagnosis is primarily made from clinical presentation. While definitive diagnosis of parvovirus B19 infection relies on the detection of viral DNA via PCR or DNA hybridization assays using patient serum, blood or tissue samples. Additionally, serologic detection of viral IgM or IgG antibodies via ELISA (enzyme-linked immunosorbent assay) can be used for diagnoses.

Treatment and Prevention

At present, there is no specific treatment for parvovirus B19 infections. Infection control measures are used in hospitals to avoid parvoviral spread, such as rigorous hand washing and isolation of infected patients. Although vaccines are available for dogs and cats, there is currently no parvoviral B19 vaccine available for humans.

COMPREHENSION QUESTIONS

[33.1] Which of the following statements is most accurate regarding infection with parvovirus B19?

A. Parvovirus B19 replicates in the host cell nucleus utilizing a virally encoded DNA polymerase to create a double-stranded DNA intermediate.

B. Parvovirus B19 causes severe anemia because it preferentially infects erythrocyte precursors.

C. Parvovirus B19 can be diagnosed by detection of viral RNA using PCR or hybridization assays.

D. Parvovirus B19 can cause hydrops fetalis via transplacental infection of a fetus in a seropositive mother.

E. Parvovirus B19 is transmitted primarily by fecal-oral transmission and is highly prevalent in infants and young children.

[33.2] A normally healthy 7-year-old girl is sent home from school with a suspected case of fifth disease as a result of her presenting with the initial symptoms of the infection. After being at home for a few days, her symptoms change indicating her transition into the second phase of the illness. Which of the following symptoms is the girl most likely experiencing during the second phase of parvoviral infection?

A. Aplastic crisis

B. Diarrhea

C. High fever

D. Skin rash

E. Swollen glands

[33.3] Which of the following conditions would put an individual at increased risk for serious chronic illness following an infection with parvovirus B19?

A. Immunization with a live measles vaccine

B. Having sickle cell disease

C. Caring for a pet with canine parvoviral infection

D. Coinfection with influenza A virus

E. Not being immunized for poliovirus

Answers

[33.1] B. Parvovirus B19 binds preferentially to the erythrocyte blood group P antigen on erythroid precursor cells; answers A, B, C, and E are incorrect: (A) after entry the single-stranded viral DNA genome is transported to the cell nucleus where the host DNA polymerase synthesizes the complimentary DNA strand; (C) Parvovirus B19 infection can be diagnosed by direct detection of viral DNA not RNA; (D) the fetus of a seropositive mother is protected from infection by maternal circulating antibodies; (E) Parvovirus B19 is transmitted primarily by respiratory secretions and is prevalent in school-age children.

[33.2] D. The second stage of parvoviral B19 infection is immune-mediated, and results in formation of a lacy skin rash occurring first on the face and then moves to the extremities; answers A, B, C, and E are incorrect: (A) aplastic crisis occurs in hosts with sickle cell disease or other acquired hemolytic anemias, not in normally healthy individuals; (B) parvoviral infection does not cause gastrointestinal symptoms; (C) mild fever, not high fever, is a symptom that occurs in the initial stage of fifth disease; (E) parvoviral infection does not result in swollen glands.

[33.3] B. More serious complications of parvoviral B19 infection, such as aplastic crisis, can occur in hosts with sickle cell disease or other chronic hemolytic anemias; answers A, C, D, and E are incorrect as they are not associated with serious complications of parvovirus B19 infection.

MICROBIOLOGY PEARLS ❖ Parvovirus B19 is the smallest human DNA virus and replicates in mitotically active erythroid progenitor cells. ❖ Clinical manifestations in children: mild fever followed by rash with “slapped cheek” appearance; fetal infections: hydrops fetalis and death. ❖ Clinical manifestations in adults: polyarthritis of hands, knees, and ankles with or without rash; chronic infection may result in chronic anemia or aplastic crisis. ❖ No specific treatment or vaccination.

REFERENCES

Brooks GF, Butel JS, Morse SA. Jawetz, Melnick, & Adelberg’s Medical Microbiology, 23rd ed. New York: McGraw-Hill, 2004:414–9. 

Heegaard ED, Hornsleth A. Parvovirus: the expanding spectrum of disease. Acta Paediatr 1995;84:109–17. 

Ryan JR, Ray CG. Sherris Medical Microbiology, 4th ed. New York: McGraw-Hill, 2004:522–3.

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